The present invention relates to a pharmaceutical composition for application to the mucosa to be used in drug therapy comprising a water-insoluble and/or water-low soluble substance, ciclesonide, and an aqueous medium, and having an osmotic pressure of less than 290 mOsm. More specifically, the present invention relates to a pharmaceutical composition for application to the mucosa comprising a water-insoluble and/or water-low soluble substance, ciclesonide, and an aqueous medium, and having an osmotic pressure of less than 290 mOsm, that is superior to conventional pharmaceutical compositions for application to the mucosa, due to ciclesonide retentivity and high ciclesonide permeability to the submucosa and the blood at the mucosa.
Application to the mucosa as a method of drug therapy has been recognized as a useful means of medication for such reasons as (1) it permits direct application to the affected area for diseases of local areas such as nasal mucosa, oral mucosa, and vaginal mucosa, (2) its immediate effects for systemic diseases can be expected as in the case of a nasal spray to the nasal mucosa and a suppository to the rectal mucosa, and (3) its application is easy compared to injection, as represented by an oral drug targeted at the intestinal mucosa, and the like. For example, pharmaceutical preparations for application to the mucosa have already been commercially available due to reason (1) in the case of nasal sprays for treatment of allergic rhinitis, and due to reason (2) in the case of suppositories to alleviate pain.
As pharmaceutical preparations for local mucus diseases, Saunders et al., (WO 92-14473), for example, provides a suspension preparation containing Tipredane as the main drug as the pharmaceutical preparation for treatment of allergic rhinitis. Also, Helzner et al., (WO 97-01337) provides a pharmaceutical preparation comprising an antihistaminic drug, a steroid and water as the pharmaceutical preparation for treatment of allergic rhinitis.
As the pharmaceutical preparations for systemic diseases, several methods have been provided that enhance the absorption of drugs through the mucosa. Nagata et al. (Japanese Unexamined Patent Publication (Kokai) No. 63 (1988)-303931), for example, provides a method of applying to the nasal cavity a growth hormone-releasing factor at the liquid form having an osmotic pressure ratio of 1 (an osmotic pressure of 290 mOsm) or lower as a method for enabling quick and efficient absorption of the a growth hormone-releasing factor through the nasal mucosa to the blood circulation. Furthermore, Ohwaki et al. (Japanese Unexamined Patent Publication (Kokai) No. 60 (1985)-123426) provides a method of applying to the nasal cavity a solution of secretin having an osmotic pressure ratio of 1 to 5 (an osmotic pressure of 290-1450 mOsm) and a pH of 2 to 5 as a method for enabling quick absorption of secretin through the nasal mucosa to blood circulation. Furthermore, Awatsu et al. (Pharm. Res. Vol. 10, No. 9, 1372-1377, 1993) provides a method of applying to the nasal mucosa a pharmaceutical solution to which polyoxyethylene 9-laurylether was added as an absorption enhancer as a method for enabling efficient absorption of a granulocyte colony-stimulating factor through the nasal mucosa to blood circulation.
Ciclesonide is a newly generated lipophilic corticoid. Due to its bioactivity, a commercially available ciclesonide contained pharmaceutical preparation for topical or systemic diseases is expected.
However, when a ciclesonide contained pharmaceutical preparation same composition as the conventional one is given to the mucosa, liquid-dripping can occur, or the pharmaceutical preparations are quickly excreted to the outside of the mucus tissue due to a mucociliary clearance function etc. before being adequately transported or permeated to the mucosa tissue. The method of using an absorption enhancer is yet to be realized because the absorption enhancer has the problem of irritating the nasal mucosa.
Thus, it is strongly desired to develop a ciclesonide contained pharmaceutical preparation for application to the mucosa, that allows the transport of an adequate amount of ciclesonide through the mucosa to the submucosa or the blood after the application to the mucosa.
The object of the present invention is to provide a pharmaceutical composition for application to the mucosa, that has efficient and high ciclesonide permeability through the mucosa to the submucosa or the blood when applied to the mucosa.
After intensive studies to attain the above first object, the present inventors have found that it is possible to provide a ciclesonide contained pharmaceutical preparation for application to the mucosa that is superior over conventional liquid composition due to efficient and high permeability through the mucosa to the submucosa or the blood, by formulating ciclesonide that contains a water-insoluble and/or water-low soluble substance and that has an osmotic pressure of less than 290 mOsm, and thereby have reached the present invention.
An enhanced absorption of a drug through the mucosa by controlling the osmotic pressure of a pharmaceutical preparation is disclosed in a patent to Osada or Ohwaki and has been reported in a paper by Awazu et al. (Pharm. Res. Vol. 10, No. 9, 1372-1377, 1993). However, these phenomena are only observed in aqueous solution preparations that do not contain a water-insoluble and/or water-low soluble substance, and thereby are essentially different from the ciclesonide contained pharmaceutical preparation of the present invention in which the inclusion of a water-insoluble and/or water-low soluble substance is essential. Furthermore, it has been shown in Osada""s patent that absorption through the rat nasal mucosa of growth hormone releasing factor is higher when the preparation has an osmotic pressure ratio of 1 (osmotic pressure of 290 mOsm) or lower, and in Ohwaki""s patent it is higher when secretin has an osmotic pressure ratio of 1 (osmotic pressure of 290 mOsm) or greater, and in Awazu""s patent the absorption of granulocyte colony-stimulating factor is higher when the preparation has an osmotic pressure of 285 mOsm than 174 mOsm. So one cannot expect the fact that the ciclesonide absorption enhanced with decreasing an osmotic pressure.
The patent application by Saunders (WO 92-14473) and Helzner (WO 97-01337) described above describe pharmaceutical preparations containing a water-insoluble and/or water-low soluble substance. However, Saunders"" patent application (WO 92-11473) makes no description of osmotic pressure of pharmaceutical preparations in general, in its claim, and merely describes in the specification that isotonicity is preferred, and Helzner""s patent application makes no description of osmotic pressure of pharmaceutical preparations in general, and merely describes in the specification that the addition of an isotonic agent is preferred. From these patents, therefore, one cannot expect a drastic enhancement in the ciclesonide absorption at low osmotic pressures.
It is surprising therefore that the effect of enhancing the ciclesonide absorption at lower osmotic pressure through the mucosa is drastic when a water-insoluble or water-low soluble substance is coexistent.
Thus, the present invention provides an aqueous pharmaceutical composition for application to the mucosa comprising one or more water-insoluble substance and/or water-low soluble substance and ciclesonide, and having an osmotic pressure of less than 290 mOsm. The composition is a pharmaceutical composition for application to the mucosa that is superior over conventional pharmaceutical compositions for application to the mucosa, due to markedly efficient and high ciclesonide permeability to the submucosa or the blood at the mucosa.